Selective dorsal rhizotomy in Hong Kong: multidimensional outcome measures

We prospectively case series study evaluated the short-term effectiveness of selective dorsal rhizotomy plus physiotherapy. Twenty children with spastic cerebral palsy, selected for selective dorsal rhizotomy (mean age, 8.57 years; range, 5.96-11.18 years), were assessed before, and 6 and 12 months after, selective dorsal rhizotomy. Main outcome measures included the Modified Ashworth Scale, passive range of joint movement, the Gross Motor Function Measure, the Pediatric Evaluation of Disability Inventory, the Canadian Occupational Performance Measure, and three-dimensional gait analysis. The results confirmed that selective dorsal rhizotomy plus physiotherapy provided a statistically significant reduction of spasticity, functional improvements in mobility and self-care performance, and increased participation in social situations in our study group (85% exhibited normal intelligence, and 90% belonged to Gross Motor Function Classification System levels I-III). The Gross Motor Function Measure proved to be sensitive in documenting motor functional changes, except for children at Gross Motor Function Classification System level I. Instrumental three-dimensional gait analysis with kinematics and kinetics data analysis confirmed gait improvements in children of higher motor function. The Canadian Occupational Performance Measure indicated improvements in social participation.     

Laparoscopic gastric bypass at a large academic medical center: lessons learned from the first 1000 cases

Bariatric surgery is an effective and durable treatment for morbid obesity in properly selected patients. Surgical outcomes and patient management methods should routinely be reviewed to improve patient care and maintain long-term effectiveness of the bariatric operation. Over a 5-year period, 1096 laparoscopic Roux-en-Y gastric bypass operations were performed at our institution. A comprehensive prospective database was maintained, which included data for comorbidities, operative techniques, perioperative management, complications, and follow up. Many practice patterns such as the omission of routine preoperative sleep apnea testing and biliary ultrasounds remained constant and were validated by the outcomes measured. Several changes, however, were implemented based on outcomes analyses, including antecolic placement of the roux limb, a pars flaccida approach to the creation of the gastric pouch, longer alimentary limbs in superobese patients, and a selective approach to postoperative upper gastrointestinal imaging. Postoperative weight regain and inability to maintain long-term follow up in a significant per cent of patients were two identified and ongoing problems. Maintenance of a bariatric patient database is essential with its routine review resulting in changes to practice patterns and operative techniques. An effective method for long-term patient follow up remains elusive and may contribute to postoperative weight regain in some patients.     

Glucose metabolism in vivo in four commonly used inbred mouse strains

OBJECTIVE—To characterize differences in whole-body glucose metabolism between commonly used inbred mouse strains.RESEARCH DESIGN AND METHODS—Hyperinsulinemic-euglycemic (∼8.5 mmol/l) and -hypoglycemic (∼3.0 mmol/l) clamps were done in catheterized, 5-h-fasted mice to assess insulin action and hypoglycemic counter-regulatory responsiveness. Hyperglycemic clamps (∼15 mmol/l) were done to assess insulin secretion and compared with results in perifused islets.RESULTS—Insulin action and hypoglycemic counter-regulatory and insulin secretory phenotypes varied considerably in four inbred mouse strains. In vivo insulin secretion was greatest in 129X1/Sv mice, but the counter-regulatory response to hypoglycemia was blunted. FVB/N mice in vivo showed no increase in glucose-stimulated insulin secretion, relative hepatic insulin resistance, and the highest counter-regulatory response to hypoglycemia. In DBA/2 mice, insulin action was lowest among the strains, and islets isolated had the greatest glucose-stimulated insulin secretion in vitro. In C57BL/6 mice, in vivo physiological responses to hyperinsulinemia at euglycemia and hypoglycemia were intermediate relative to other strains. Insulin secretion by C57BL/6 mice was similar to that in other strains in contrast to the blunted glucose-stimulated insulin secretion from isolated islets.CONCLUSIONS—Strain-dependent differences exist in four inbred mouse strains frequently used for genetic manipulation and study of glucose metabolism. These results are important for selecting inbred mice to study glucose metabolism and for interpreting and designing experiments.The development of new mouse models has allowed investigators to address questions related to glucose metabolism in ways that were not previously possible. Use of inbred mouse strains and proliferation of techniques to produce genetic modifications have been invaluable in defining the role of select genes under physiological conditions. To rigorously examine complex physiological processes in vivo has required the development of new experimental approaches for the mouse and the adaptation of techniques previously used in larger animals. Important technical advancements, including surgical catheterization (1) and miniaturization of clamp techniques (2) for the mouse, have furthered our ability to dissect the physiology underlying insulin action, insulin secretion, and counter-regulation to insulin-induced hypoglycemia under well-controlled physiological conditions.Mouse models produced through genetic modification have been generated in a variety of mouse strains. It is widely recognized that the background mouse strain can influence phenotypes. Several examples have been described where identical genetic mutations in different inbred mouse strains result in different phenotypes (3–5). These findings indicate that the contribution of the inbred strain genetic background to the phenotype is an important factor to consider when designing and interpreting experiments.The goal of the current studies was to define the glucoregulatory phenotype of four commonly used inbred mouse strains under well-controlled conditions. We investigated insulin action using the hyperinsulinemic-euglycemic clamp, counter-regulatory response during an insulin-induced hypoglycemic clamp, and insulin secretion during a hyperglycemic clamp. Insulin secretion assessed in vivo was compared with insulin secretion in perifused islets.     

Examining differences in weekly warfarin dose in patients with and without cancer

The incidence of thrombosis and bleeding is higher in patients with cancer receiving warfarin compared with low molecular weight heparins. Despite these findings, warfarin remains a commonly used treatment strategy for anticoagulation in patients with cancer secondary to several factors that limit the use of low molecular weight heparins. Determining the appropriate warfarin dose in cancer patients is challenging. The objective of our study is to compare the weekly warfarin dose in patients with and without cancer. In a retrospective analysis, the average weekly warfarin dose was compared for 63 subjects who 1) were treated for cancer while receiving warfarin (n = 21), 2) completed treatment for their cancer before starting warfarin (n = 21), and 3) received warfarin with no diagnosis of cancer (n = 21). The data were abstracted from the medical record from the date the subject started taking a stable dose of warfarin after the initial titration until the discontinuation of warfarin. No significant differences were observed in the mean weekly warfarin dose, but the dose demonstrated greater intrasubject variability for subjects in group 1 (group 1, 31 +/- 22% vs. 2, 19 +/- 11% and 3, 15 +/- 10%, P = 0.003). Subjects in group 1 also spent more time above their goal International Normalized Ratio (group 1, 30 +/- 21% vs. 2, 21 +/- 16% and 3, 15 +/- 16%, P = 0.038). The average weekly warfarin dose was similar for the three groups, but the results of this study suggest that patients with cancer receiving treatment for their cancer and anticoagulation with warfarin are more difficult to appropriately anticoagulate.     

Maternal Atrial Arrhythmia Detected by Uterine Artery Doppler

BackgroundUterine artery Doppler ultrasound assessment is used to assess uteroplacental blood flow and the risk of placental ischemic-thrombotic injury in high-risk pregnancies. We report here a case in which this examination identified the presence of a maternal atrial arrhythmia.CaseA 50-year-old woman with no significant past medical history received antenatal care in our fetal medicine unit clinic because of advanced maternal age, a history of recurrent pregnancy loss, multiple uterine fibroids, and a history of in vitro fertilization using donated oocytes. Uterine artery Doppler ultrasound was normal at 19 weeks, but was repeated at 33 weeks because of abnormal placental texture and maternal risks, revealing an irregular maternal heart rhythm. Paroxysmal atrial fibrillation was confirmed by Holter monitor at 34 weeks. The patient was asymptomatic and declined the cardiologist’s recommendation of antepartum and postpartum anticoagulation. She remained asymptomatic and had delivery by Caesarean section at term.ConclusionUterine artery Doppler flow studies may identify a significant maternal cardiac arrhythmia.     

Chondromyxoid fibroma of the nasal cavity and palate

We present an exceedingly rare case of chondromyxoid fibroma of the nasal cavity and palate. This rare tumor usually occurs in the metaphyses of the long bones. Our patient's tumor was diagnosed by biopsy, and it was resected en bloc. At the 2-year follow-up, the patient was doing well with no signs of recurrence. We review the pathologic characteristics, differential diagnosis, and treatment of chondromyxoid fibroma of the nasal cavity.     

WGA allows the molecular characterization of a novel large CFTR rearrangement in a black South African cystic fibrosis patient

By performing extensive scanning of whole coding and flanking sequences of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene, we had previously identified the CF-causing mutations in black South African patients of different ethnic groups suspected with the disease. Of ten samples analyzed, there were six remaining that had either one (n = 2) or two (n = 4) unidentified CFTR alleles that have now been tested for large rearrangements using a semiquantitative fluorescent PCR assay. A novel deletion encompassing CFTR exon 2 was detected in one patient who was heterozygous for the mutation 3120+1G>A. The Caucasian deletion involving the same exon [c.54-5811_c.164+2186del8108ins182] was ruled out. The DNA had been stored for more than 12 years and only minute quantities remained. We thus used a whole-genome amplification method based on multiple displacement amplification to generate sufficient amounts of DNA to characterize the intronic breakpoints and identify the deletion at the genomic level. Mapping and sequencing the breakpoint junctions revealed a novel large deletion [c.54-1161_c.164+1603del2875]. We have designed a simple test to specifically detect the presence or absence of this large rearrangement. This study reports the first large CFTR rearrangement in a black South African CF patient, further defining the molecular spectrum of CF that will be useful for improving genetic testing and counseling in this region.     

AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies

Insights from cell cycle research have led to the hypothesis that tumors may be selectively sensitized to DNA-damaging agents resulting in improved antitumor activity and a wider therapeutic margin. The theory relies on the observation that the majority of tumors are deficient in the G1-DNA damage checkpoint pathway resulting in reliance on S and G2 checkpoints for DNA repair and cell survival. The S and G2 checkpoints are regulated by checkpoint kinase 1, a serine/threonine kinase that is activated in response to DNA damage; thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death. Normal tissues, however, have a functioning G1 checkpoint signaling pathway allowing for DNA repair and cell survival. Here, we describe the preclinical profile of AZD7762, a potent ATP-competitive checkpoint kinase inhibitor in clinical trials. AZD7762 has been profiled extensively in vitro and in vivo in combination with DNA-damaging agents and has been shown to potentiate response in several different settings where inhibition of checkpoint kinase results in the abrogation of DNA damage-induced cell cycle arrest. Dose-dependent potentiation of antitumor activity, when AZD7762 is administered in combination with DNA-damaging agents, has been observed in multiple xenograft models with several DNA-damaging agents, further supporting the potential of checkpoint kinase inhibitors to enhance the efficacy of both conventional chemotherapy and radiotherapy and increase patient response rates in a variety of settings.     

Partner outcomes from an uncontrolled trial of Couple HOPES: A guided online couple intervention for posttraumatic stress disorder and relationship enhancement

Posttraumatic stress disorder (PTSD) is associated with significant individual and relationship impairment for people with PTSD and their romantic partners. Conjoint treatments, such as cognitive behavioral conjoint therapy for PTSD (CBCT), are designed to address individual and relationship factors, yet significant barriers impede accessing in-person therapy. Couple HOPES (i.e., Helping Overcome PTSD and Enhance Satisfaction) is a coach-guided, online couple intervention for PTSD based on CBCT that was designed to address these barriers. Previous investigations have found preliminary efficacy of Couple HOPES for improving PTSD symptoms, relationship functioning, and some individual functioning domains for the partner with probable PTSD. However, no study to date has tested individual outcomes for romantic partners, which is needed to fully evaluate the intervention's promise. The current study tested these partner outcomes in a combined, uncontrolled sample of 27 couples. Intent-to-intervene analyses found significant improvements at postintervention in four of eight tested outcomes, including ineffective arguing, g = 0.74; anger, g = 0.32; perceived health, g = 0.67; and quality of life, g = 0.56. Depressive symptoms, generalized anxiety, alcohol misuse, and work functioning did not significantly change, gs = 0.17–0.42. Among participants who completed a 1-month follow-up assessment, generalized anxiety, g = 0.43, and perceived health, g = 0.73, significantly improved over follow-up, whereas anger, g = -0.48, lost gains previously made. Results were largely consistent in the completer sample. These findings show the potential of Couple HOPES to have broad benefits not only for individuals with probable PTSD but also for their romantic partners.